Development of osteopenia (bone loss) in postmenopausal women can be successfully prevented by therapy with tamoxifen (TAM), and possibly with related triarylethlyenes clomiphene (CLO) and toremifene (TOR). Similar results were seen in the ovariectomized (OVX) rat, the best animal model for osteopenia. In this application, we propose experiments in OVX rats to test whether TAM and its analogues owe their bone-protective effects, in part, to multistep biotransformation affording novel estrogenic metabolites. These metabolites were suggested, on the basis of chromatographic studies of TAM and TOR elimination from rats, to be produced from each of the respective parent drug by formal replacement of the basic either side chain with an oxyacetic acid moiety, with or without p-hydroxylation of the ring germinal to the one bearing the side chain. SPECIFIC AIMS: (A) to isolate an spectrally characterize these oxyacetic acid metabolites as elimination products of TAM and CEO in the OVX rat, in ways similar to those used to identify such metabolites already known to be produced from TOR; (B) to determine how the estrogen receptor affinities and estrogenic potencies/efficacies of oxyacetic metabolites of CEO and TOR compare wit those established for analogous metabolites of TAM, in an estrogen responsive cell line; (C) to compare active metabolites of CEO and TOR with TAM itself in regard to effects on bone histomorphometry in the OVX rat. Comparison will also be made with data obtained from animals receiving an oxyacetic acid metabolite of TAM known to be devoid of estrogenic activity, in order to confirm that effects are mediated via estrogen receptors. Results of these studies could serve as a basis for development of new drugs for treatment of osteoporosis and related diseases.